The present invention relates to a pharmaceutical preparation adhering to the skin, in particular a transdermal therapeutic system, for the release of 17-xcex2-estradiol and optionally further active substances through the skin to the human organism.
Pharmaceutical preparations contacting the skin include, for example, ointments, creams, lotions, and also drug-containing patches, these have been introduced on the market for some time under the name xe2x80x9ctransdermal therapeutic systemsxe2x80x9d (TTS) to treat several diseases.
In the meantime, TTSs comprising the active substance 17-xcex2-estradiol have also been on the market as a therapeutic agent for climacteric complaints, and, for a short time, also against osteoporosis, proving successful in therapy.
In several cases, however, the insufficient capability of the active substance to permeate through the skin has become apparent as a disadvantage of prior art systems. This cannot be increased beyond a certain limit, the so-called xe2x80x9csaturation flowxe2x80x9d, although numerous galenic measures with respect to the TTS-construction have been taken (use of multilayer systems, use of controlling membranes, variations of the active substance concentration, modification of the base polymer, and the like).
The finding that the transdermal flow of an active substance from the solid, finely dispersed phase cannot be increased further, even if high-dissolving vehicles are used, can already be found in the trailblazing works of Higuchi (e.g., T. Higuchi: Physical Chemical Analysis of percutaneous absorption process from creams and ointments, J. Soc. Cosmetic Chem. 11 p. 85-97 (1960). However, for many active substances there is the possibility of adding so-called xe2x80x9cenhancersxe2x80x9d to the TTS during its production. In general, these are liquid additives improving the absorption properties of human skin so that the active substance can be absorbed from a sufficiently small TTS-surface.
In particular readily volatile enhancers, e.g., ethanol frequently used for the active substance 17-xcex2-estradiol, cause problems due to extreme softening of the patches"" adhesive layers, therefore they require additional bulky compartments in the system, rendering the TTS unacceptably thick or voluminous. Finally, any additional non-polymeric additive involves the risk of intolerance phenomena on the skin, possibly even that of sensitization. The addition of less volatile, however, mostly less active enhancers (e.g., glycerol esters, cyclic amides, eucalyptol) makes it possible to produce matrix systems comprising the active substance and absorption-promoting components in one or several monolithic layers. However, the adhesive strength of the patch remains unsatisfactory.
U.S. Pat. No. 4,863,738 represents one of many examples claiming the application of an active substance, e.g., 17-xcex2-estradiol, together with an enhancer (in this case glycerol monooleate) in an optional concentration within a TTS-matrix.
According to the art, these TTSs do not permit a satisfactory therapy, either because the chosen enhancers have a poor skin tolerance, or the systems must have unacceptably large surfaces owing to insufficient active substance flow through the skin.
Dissolving more active substance molecularly disperse in the TTS than corresponds to the saturation solubility might be another possibility of increasing the active substance flow through the skin. With the degree of supersaturation of these systems the permeation rate through the skin is increased to the same extent. However, since supersaturated physical states are thermodynamically unstable, these forms of administration are not stable in storage. Spontaneous, unforeseeable precipitations of active substance particles will take place within months, or not later than years, so that the flow rate through the skin gradually decreases to the saturation flow level and a great deal of the initially existent therapeutic activity is lost.
The systems described in EP 0 421 454 comprise 17-xcex2-estradiol in an acrylate polymer under addition of xe2x80x9ccrystallization inhibitorsxe2x80x9d and tackifying resins. Swelling agents are contained to give protection against premature loss of adhesive force.
A completely different way of avoiding thermodynamic instability js opened up in DE 42 37 453. It describes a transdermal therapeuticsystem having an active substance concentration ranging between the saturation solubility under moist conditions and that under dry conditions. A maximum ambient humidity of 10% is meant by xe2x80x9cdryxe2x80x9d conditions, and the achieved increase of skin permeation is stated to be about 50%.
It is the object of the present invention to provide a pharmaceutical preparation which, as compared to the prior art, results in higher active substances flows through the skin and does not undergo activity losses owing to recrystallization or active substance precipitation during storage.
According to the present invention this object is achieved in a pharmaceutical preparation according to the introductory part of claim 1 by the characterizing features stated in claim 1, by the fact that the estradiol amount contained in the preparation amounts to at least three times the saturation solubility amount measured at 95% atmospheric humidity, and that the air present in the package is adjusted to a relative air humidity of below 5%, preferably below 2% relative air humidity.
At room temperature and a relative air humidity between 20 and 60%, 17-xcex2-estradiol is not present in an anhydric modification (I and 11), but as a semihydrate (Busetti and Hospital, Acta Cryst. 1972, B28, 560). Owing to the layered structure stabilized via hydrogen bridges, and because of the diffusional compactness of the crystal compound, the hydrate can be subjected to a short-term heat treatment to temperatures of up to 170xc2x0 C. without decomposition (Kuhnert-8randstatter and Winkler (1976), Scientia Pharmaceutica 44 (3), 177-190).
With decreasing partial water vapor pressure, on the other hand, 17-xcex2-estradiol has a higher solubility in some polymers, particularly in acrylate copolymers and in mixtures of rubbers and resins, polyvinyl acetate, polyvinyl alcohols, in polyvinyl pyrrolidone and mixtures or copolymers thereof, as well as in silicone polymers.
The fact that 17-xcex2-estradiol, under the conditions indicated above, has a higher solubility in some polymers, particularly in acrylate copolymers, has already been known from DE 42 37 453; however, the extent of solubility increase to more than three times the amount has not been expected and is most surprising (Example 1), even in consideration of the art. According to Fick""s law, higher active substance concentrations in a TTS with otherwise same conditions increase the diffusion flow through the skin; for this reason, such a concentration increase in transdermal therapeutic systems is very advantageous. Thus, preparations manufactured according to the present invention can develop the same efficacy as prior-art systems, but with a smaller surface. However, absolute dry storage conditions are required to stabilize these properties.
These can preferably be ensured by gasproof and moistureproof packages, and by inserting moisture-absorbing products into the packing.
The above-described invention may be realized in pharmaceutical preparations in different manners.
In an ointment, 17-xcex2-estradiol is homogeneously distributed as an anhydrate or semihydrate according to usual methods by stirring under heating and adding to the ointment base an estradiol solution in a solvent, or by dispersing the micronized active substance. The simplest form of a percutaneous skin-adherent pharmaceutical preparation is a single-layer matrix system whose matrix, in addition to its function of delivering active substances, is pressure-sensitive adhesive at the same time, rendering an adhesive layer superfluous. However, the system may also be divided into several layers of the same or different composition and function.
If a membrane, which is poorly permeable to estradiol, is placed between such a matrix and a skin-facing adhesive layer, an active substance release is obtained which is controlled to a greater extent by the patch than by the skin. Such an active substance release may be advantageous if a very narrow margin of daily dosage is desired.
For use in the matrix layer or layers and, if present, in the adhesive layer,
mixtures of rubbers and resins;
polyvinyl acetate, polyvinyl alcohols, polyvinyl-pyrrolidone and mixtures or copolymers thereof; and
silicone polymers
are especially suitable as base materials. However, many other base materials, which are compatible with the skin, are also suitable. The aforementioned materials can also be used as mixtures or in combination.
Rubbers may be natural rubber as well as synthetic rubbers, including polystyrene-based rubbers such as styrene-isoprene-styrene (SIS) copolymers or styrene-butadiene-styrene (SBS) copolymers, polyisobutylene, polybutene, polyisoprene, silicone rubbers, and the like.
Resins which are particularly suitable are colophony (rosin) or colophony derivatives (rosin derivatives) as, for example, esters of colophony, rosin alcohols, hydrogenated colophony, and derivatives thereof, derivatives of abietyl alcohol and of xcex2-pinene, as well as hydrocarbon resins (saturated or unsaturated), e.g., polyterpene resins, as well as petroleum rsins, coumarone-indene resins, terpene phenol resins. However, the invention is not limited to the selection of the above-mentioned resins. Generally, all types of resins may be used which asr known to the skilled person as xe2x80x9ctackifying resins.xe2x80x9d
Silicone polymers may be present in said layer(s) in the form of silicone adhesives or, if present in the matrix layer or layers, as more or less rigid gel-like or rubber-like polymerisates. For example, pressure-sensitive adhesives based on a polydimethylsiloxane structure can be used.
Acrylate copolymers are copolymers formed by radical polymerization of esters of acrylic acid and/or of methacrylic acid with C1 to C18-alcohols, dimethylaminoethanol, or other suitable alcoholic reactants, vinyl acetate, vinyl pyrrolidone, styrene, butadiene, acrylonitrile, or other suitable monomers with a vinyl group.
To render the system softer, 1,2-propanediol, 1,3-butylene glycol, 1-hexadecanol may be added, for example; or also 2-hydroxyfatty alcohols, 2-octyl dodecanol, 2-propanol, benzyl alcohol, cetylstearyl alcohol, diethylene glycol, dipropylene glycol, dodecanol, ethanol, glycerol, hexanediol, octanol, oleyl alcohol, panthenol, phenylethanol, polyethylene glycols, or polypropylene glycols; or fatty acids, such as, capric, linoleic, lauric, myristic acid, n-valeric acid, pelargonic acid; and also physiologically acceptable organic acids, such as, 3-phenylpropionic acid, acetic acid, adipic acid, benzoic acid, oleic acid, salicylic acid, or their salts well tolerated by the skin. Other compounds of this kind includexe2x80x94without claiming completenessxe2x80x94sulfates and sulfonates of fatty acids, esters of the formula [CH3(CH2)mCOO]R, wherein m represents a number of 8 to 16, n 1 or 2, and R a short-chain alkyl chain; triglycerides, phthalates, sulfoxides, or amides.
Furthermore, the addition of up to 40% wt. of fillers, such as titanium dioxide, zinc oxide, chalk, activated charcoal, finely divided silicium dioxide, etc., does by no means impair the function of the pharmaceutical preparations according to the present invention, and may be advantageous with respect to the cohesion of the finished product.
Typically, the transdermal systems further comprise a film-like removable protective layer which covers the adhesive layer during storage and which is removed before the system is applied to the skin of a patient. The material used for the removable protective layer is of less importance for the function of the transdermal system. The protective layer may, for instance, consist of a polyester material, e.g., polyethylene terephthalate. However, other skin-compatible plastics may also be used, such as polyvinyl chloride, polyvinylidene chloride, ethylene vinylacetate, polyethylene, polypropylene, cellulose derivatives, laminates of those materials, and many other materials may be used. In particular cases, the protective layer could be metallized or treated by vapor-plating with other diffusion-blocking additives, such as silicon dioxide, aluminium oxide, and the like. In any case, the surface facing the adhesive matrix must be treated with dehesive (release) materials, such as silicones or fluorine-containing compounds, so that the protective layer remains easily removable.
The thickness of the film-like, removable protective layer normally amounts to about 40 to 200 xcexcm; however, for special purposes, it may also be thicker or thinner than that.
The present invention will be illustrated in greater detail in the following with reference to Examples.